Empirical Treatment With Micafungin For At-Risk Patients With Suspected Invasive Candidiasis

Rick Hessler, Mercer University College of Pharmacy

According to the Infectious Diseases Society of America’s (IDSA) clinical practice guideline for the management of candidiasis, empiric antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis.  It has been suggested that therapy be started as soon as possible for patients with risk factors for septic shock. Empiric therapy for suspected candidiasis in nonneutropenic patients in the intensive care unit (ICU) is proposed to be an echinocandin (caspofungin, anidulafungin, or micafungin) for two weeks. [1]

Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure [2]
Design Multicenter, double-blind, placebo-controlled; N= 235
Objective To determine if empirical antifungal therapy increases invasive fungal infection–free survival at day 28
Study Groups Micafungin 100 mg, once daily for 14 days (n= 118); placebo group (n= 117)
Methods Following randomization, a set of blood cultures was prepared using aerobic, anaerobic, and selective milieu before administration of the study drug.  If invasive candidiasis was evidenced, study treatment was withdrawn and the standard antifungal treatment of the investigation site was administered.  Subgroup analysis was performed based on patient’s Sequential Organ Failure Assessment (SOFA) score, admission category, Candida score, and colonization index.
Duration July 20, 2012 – February 7, 2015
Primary Outcome Measure 28-day survival, free of proven invasive fungal infection
Baseline Characteristics Micafungin Placebo
Mean age, years (range) 65 (56-74) 64 (52-74)
Men, n (%) 163 (65) 82 (64)
Admission Category
Medical, n (%) 92 (75) 94 (73)
Emergency surgery, n (%) 29 (24) 31 (24)
Scheduled surgery, n (%) 2 (2) 3 (2)
SOFA score, median (IQR)a 8 (5-12) 8 (6-11)
Candida score, median (IQR)b 3 (2.5-4) 3 (2-4)
Positive colonization sites, median (IQR) 3 (2-4) 3 (2-4)
Results Micafungin – Survival at day 28, n Placebo – Survival at day 28, n Hazard Ratio (95% CI)
SOFA Score ≤ 8 51 52 1.35
SOFA Score > 8 36 22 1.69
Admission Category
Surgical 22 16 1.56
Medical 65 58 1.43
Colonization Index ≥ 0.5c 68 58 1.35
Candida score ≥ 3 64 47 1.37
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions When compared with placebo, empirical treatment with micafungin did not increase fungal infection-free survival at day 28 in nonneutropenic critically ill patients with ICU-acquired sepsis, Candida species colonization at multiple sites, and multiple organ failure.

a Higher score indicate worse outcome (SOFA range, 0-24)

b Candida score (range, 0-5) items are surgical admission (1 point), severe sepsis (2 points), multiples sites positive with Candida species (1 point), and parenteral nutrition (1 point)

c Colonization index (range, 0-1) indicates the number of positive sites colonized with Candida divided by the number of sites sampled.

A modest but non-significant improvement was seen in the subgroup of patients with high SOFA scores, suggesting that these increasingly ill patients stand to receive more benefit from antifungal agents.  The study findings call into question the use of empiric antifungal therapy in the trial patient population, especially when considering potential for benefit as well as limiting the patient’s financial burden.

References

  1. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50.
  2. Timsit JF, Azoulay E, Schwebel C, et al. Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial. JAMA. 2016;316(15):1555-1564.
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